The antimanic-like effect of tamoxifen: Behavioural comparison with other PKC-inhibiting and antiestrogenic drugs.
Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150 mg/kg, i.p.), tamoxifen (1.0 mg/kg, i.p.) and chelerythrine (1 microg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0 mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0 mg/g) and higher (6.0 mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.
Sabioni
Pamela
P
Department of Pharmacology, Universidade Federal do Paraná, Setor de Ciências Biológicas, Centro Politécnico C.P. 19031, 81540-990 Curitiba, PR, Brazil.
Baretta
Irinéia P
IP
Ninomiya
Ester M
EM
Gustafson
Lianna
L
Rodrigues
Ana Lúcia S
AL
Andreatini
Roberto
R
D000661:Amphetamine; D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects*; D053119:Benzophenanthridines / Q000494:pharmacology; D003280:Contraceptives, Oral, Synthetic / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy*; D016651:Lithium Carbonate / Q000494:pharmacology / Q000627:therapeutic use; D008525:Medroxyprogesterone / Q000494:pharmacology*; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use*
D018692:Antimanic Agents; D053119:Benzophenanthridines; D003280:Contraceptives, Oral, Synthetic; D004791:Enzyme Inhibitors; D013629:Tamoxifen; D016651:Lithium Carbonate; D000661:Amphetamine; C016299:chelerythrine; D011493:Protein Kinase C; D008525:Medroxyprogesterone